Chemically ifoxetine is (+/−)-bis-[cis-3-hydroxy-4-(2,3-dimethyl-phenoxy)]-piperidine sulfate. According to the prior art, ifoxetine specifically and selectively blocks 5-HT reuptake in the brain without affecting the 5-HT uptake processes in the periphery (blood platelets). See Delini-Stula et al., Int Clin Psychopharmacol. 1987 July; 2(3):201-15, herein incorporated by reference in its entirety. The prior art also states that ifoxetine displays weak or no interactions with 5-HT1, 5-HT2, alpha1, alpha2, beta-noradrenoceptors, histamine H1, muscarinic acetylcholine, opiate, GABAA, and benzodiazepine receptors in vitro, and with doparine and 5-HT2 receptors in vivo. See Waldmeier et al., Eur J Pharmacol. 1986 Oct. 14; 130(1-2):1-10, herein incorporated by reference in its entirety (“Waldmeier”).
The synthesis of ifoxetine is disclosed in U.S. Pat. No. 4,160,837 (“Paioni”), herein incorporated by reference in its entirety. Specifically, Paioni disclosed that that certain 4-aryloxy-3-hydroxypiperidines (1), where Ar is a substituted or unsubstituted aromatic hydrocarbon group and R is hydrogen or methyl, possess valuable pharmacological properties, and can be used for the treatment of mental depression. See also Paioni and Waldmeier 1985, Proc. VIIth Int. Symp. Medicinal Chemistry (August 27-31, Uppsala, Sweden Vol. 2, eds. Dahlbom et al., Swedish Pharmaceutical Press, Stockholm, pp. 130-132, herein incorporated by reference in its entirety.

Specific embodiments described in Paioni were the dimethylphenoxypiperidines which included compounds 2-5. (Ifoxetine is racemic composition comprising the two cis diastereomers of compound 2.)

Since each of compounds 2-5 contains chiral centers at carbon 3 and carbon 4, the compounds comprise four possible diastereomers. For example the possible diastereomers of compound 2 comprise the following isomers which are shown below: 2a, (3S,4R), 2b (3R,4S), 2c (3R,4R) and 2d (3S,4S).

According to Paioni and Waldmeier et al, see supra, stereochemistry has little effect on the activity of compound 2.
The following US patents and publications describe methods, compositions, or compounds, which comprise ifoxetine. U.S. Pat. No. 6,528,521, herein incorporated by reference in its entirety, describes a method for treating sexual dysfunction that is caused by anti-depressant medication in a patient in need of such treatment, comprising administering a therapeutically effective amount of apomorphine or a pharmaceutically acceptable salt thereof, to said patient, is disclosed. The method may be utilized for patients taking anti-depressants such as tricyclic anti-depressants, monamine oxidase inhibitors or serotonin selective reuptake inhibitors (SSRI). The serotonin selective reuptake inhibitors may include ifoxetine.
U.S. Pat. No. 6,495,154, herein incorporated by reference in its entirety, describes a method for delaying the onset of ejaculation in an individual. The method involves systemic and on demand administration to an individual of a pharmaceutical formulation containing an amount of an active agent selected from the group consisting of clomipramine and pharmacologically acceptable acid addition salts thereof. Drug delivery may be accomplished via any route designed to provide systemic levels of the active agent effective to delay the onset of ejaculation. Pharmaceutical formulations and dosage forms are provided as well. In one embodiment, the pharmaceutical formulation also comprises ifoxetine.
U.S. Pat. No. 6,403,597, herein incorporated by reference in its entirety, describes a method for treatment of premature ejaculation by administration of a phosphodiesterase inhibitor, e.g., an inhibitor of a Type III, Type IV, or Type V phosphodiesterase. In a preferred embodiment, administration is on as “as needed” basis, i.e., the drug is administered immediately or several hours prior to sexual activity. Pharmaceutical formulations and packaged kits are also provided. In one embodiment, the pharmaceutical formulation also comprises ifoxetine.
U.S. Pat. Nos. 6,331,289, 6,264,917 and 6,261,537, herein incorporated by reference in their entirety, disclose targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said agent being capable of forming at least two types of binding pairs with a target. The disclosed compositions and methods may further comprise ifoxetine.
U.S. Pat. No. 6,303,595, herein incorporated by reference in its entirety, describes a method for treating sleep apneas utilizing mirtazapine. Optionally, mirtazapine is combined with an SSRI such as fluoxetine or ifoxetine.
U.S. Pat. Nos. 6,228,864 and 5,922,341, herein incorporated by reference in their entirety, describes methods for delaying the onset of ejaculation in an individual. The methods preferably involve administration of an antidepressant drug, a serotonin agonist or antagonist, an adrenergic agonist or antagonist, an adrenergic neurone blocker, or a derivative analog thereof, within the context of an effective dosing regimen. The preferred mode of administration is transurethral; however, the selected active agent may also be delivered via intracavemosal injection or using alternative routes. Pharmaceutical formulations and kits are provided as well.
U.S. Pat. No. 5,977,099, herein incorporated by reference in its entirety, describes a pharmaceutical composition comprising mirtazapine, a SSRI and pharmaceutically acceptable auxiliaries. In particular the SSRI is selected from fluoxetine, fluvoxamine, citalopram, cericlamine, femoxetine, sertraline, paroxetine, ifoxetine, cyanodothiepin and litoxetine. The composition, which can be used to treat depressant patients has less side effects than treatment of the patients with mirtazapine or the SSRI alone.
EP Patent No 835660, herein incorporated by reference in its entirety, describes products containing methylcobalamin in an overdose corresponding to a weekly intramuscular dose higher than 1000 micrograms, preferably higher than 1200 micrograms and corresponding more preferably to a weekly intramuscular dose of at least 1500 micrograms, and an antidepressant enhancing the serotonin level as a combined preparation for simultaneous, separate or sequential use in the treatment of multiple sclerosis or other demyelinating conditions. In one embodiment the 1 product comprises ifoxetine.
International application WO9200103, herein incorporated by reference in its entirety, describes a pharmaceutical product comprising two or three active ingredients as a combined preparation for simultaneous, separate or sequential use in therapy of depression and/or migraine. In one embodiment the pharmaceutical product comprises ifoxetine.
International application WO9200103, herein incorporated by reference in its entirety, describes prodrugs of antidepressants and the use of these prodrugs in a method for therapy and to pharmaceutical compositions comprising the prodrugs of the invention.